Synaptic deficits of iPS cell-derived neurons from patients with autism The goal of this proposal is to examine the physiological properties and synaptic function of ASD patient- specific neurons generated from induced pluripotent stem (iPS) cells. Many lines of evidence suggest genetic etiologies for Autism Spectrum Disorders (ASDs), but little is known about the cellular/physiological ramifications of these genetic defects. Thus, to probe the cellular basis underlying autism phenotypes, I will differentiate iPS cells from genetically defined ASD patients into neurons, and apply a combination of cutting- edge techniques including in vitro whole-cell and slide recordings, calcium imaging, and gene transfer to characterize these iPS-derived neurons. Specifically, I will study iPS cell-derived neurons from patients with point mutations or deletions in SHANK3. This gene has a key role in calcium channel function and synapse formation. I will test the hypothesis that genetic alternations in SHANK3 cause defects in the intrinsic properties and synaptic function of iPS-derived neurons from these patients. I will thoroughly investigate neuronal properties of these cell lines to provide a possible mechanistic link between the genetic alterations in the patients and their behavioral phenotypes. I will also test therapeutic strategies by using viral-mediated gene transduction to rescue neuronal phenotypes. PUBLIC HEALTH RELEVANCE Synaptic deficits of iPS cell-derived neurons from patients with autism The goal of this project is to identify biological phenotypes of neurons derived from induced pluripotent stem (iPS) cells from individuals with autism and defined genetic alterations in the SHANK3 gene. These experiments will contribute to our understanding of mechanisms underlying autism and may lead to advances in identifying new therapeutic targets and treatment strategies. They will also lay the foundation for the development of a cell-based assay system to study iPS cells and neurons from patients with a broad set of autistic spectrum disorders. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 1 Continuation Format Page